Improved process for preparing substituted crotonic acids

ABSTRACT

A process to prepare a compound of Formula (I) wherein R 3 , R 4  and R 5  are each selected independently from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxyl, and wherein the alkyl, alkenyl, alkynyl, and alkoxyl may be optionally substituted with one or more halogen, alkyl, alkenyl, alkynyl, and alkoxyl.

BACKGROUND

WO2012/041872 discloses novel N-heteroaryl compounds that are useful asmedicaments. This patent application also discloses the dehydration ofethyl 4,4,5,5-tetrafluoro-3-hydroxy-pentanoate to ethyl(E)-4,4,5,5-tetrafluoropent-2-enoate using phosphorous pentoxide (P₂O₅).

WO2012/041873 discloses novel N-heteroaryl compounds that are useful asmedicaments. This patent application also discloses the dehydration ofethyl 4,4,5,5,5-pentafluoro-3-hydroxy-pentanoate to ethyl(E)-4,4,5,5,5-pentafluoropent-2-enoate using phosphorous pentoxide(P₂O₅).

WO2013/144179 discloses novel heteroaryl compounds that are useful asmedicaments. This patent application also discloses the dehydration ofethyl 4,4 difluoro-3-hydroxy-pentanoate to ethyl(E)-4,4-difluoropent-2-enoate using diphenyl-2-pyridylphosphine anddi-butylazodicarboxylate.

WO2013/144180 discloses novel heteroaryl compounds that are useful asmedicaments. This patent application also discloses the dehydration ofethyl 4,4 difluoro-3-hydroxy-pentanoate to ethyl(E)-4,4-difluoropent-2-enoate using diphenyl-2-pyridylphosphine anddi-butylazodicarboxylate.

Jagodzinska et al. Tetrahedron 63 (2007) 2042-2046 discloses thesynthesis of crotonic acid analogues according to the following route:

wherein the dehydration reaction from C to D, the reagent used was P₂O₅.Moreover, this reference discloses that this reaction was also attemptedusing mesyl chloride and triethylamine for the transformation of C to D.However, the desired product (D) was only obtained as a minor product ina mixture of carboxylic acids. H₂SO₄, H₂SO₄/AcOH, SOCl₂ and DBU/CHCl₃were also unsuccessfully used as reagents for the dehydration reaction.R═F, H, CF₃, Cl, Br, or I.

Bevilaqua, J. Org. Chem. 49 (1984) 1430-1434 discloses a dehydrationreaction using triphenylphosphine and diethyl azodicarboxylate (DEAD) asreagents.

Tamura et al. Journal of Fluorine Chemistry 126 (2005) 918-930 disclosesa dehydration reaction using tosyl choride and triethylamine (TEA)

Yamazaki et al., Tetrahedron: Asymmetry 1 (1990) 521-524 also disclosesa dehydration reaction using tosyl choride and triethylamine (TEA).

SUMMARY OF THE INVENTION

This invention relates to an improved process for making crotonic acidintermediates which can be used to make compounds that can be used asmedicaments.

An embodiment of the invention is a process to prepare a compound ofFormula (I)

wherein R³, R⁴ and R⁵ are each selected independently from hydrogen,halogen, alkyl, alkenyl, alkynyl, alkoxyl, and wherein the alkyl,alkenyl, alkynyl, and alkoxyl may be optionally substituted with one ormore halogen, alkyl, alkenyl, alkynyl, and alkoxyl;

comprising

-   -   a) reacting a compound of Formula (V)

-   -   wherein R³, R⁴ and R⁵ are defined as above, and R⁶ is alkyl;    -   with methane sulfonyl chloride and a base to form a compound of        Formula (VI)

-   -   wherein R³, R⁴, R⁵ and R⁶ are defined as above; and    -   b) reacting the compound of Formula (VI) with a reagent to form        a compound of Formula (I).

Another embodiment of the process is wherein the base of step a) is anamine. In yet another embodiment, the amine is triethylamine.

Another embodiment of the process is wherein the reagent of step b) isan acid or a base. In yet another embodiment of the process, the reagentis a base. In further embodiments, the base is sodium hydroxide, lithiumhydroxide or potassium hydroxide. In an embodiment, the base is sodiumhydroxide.

In an alternative embodiment, the process further comprises a processfor preparing a compound of Formula (V)

wherein R³, R⁴, R⁵, and R⁶ are defined as above;comprising

-   -   i. reacting a compound of Formula (II)

-   -   wherein R³, R⁴ and R⁵ are defined as above and R⁷ is alkyl; with        a compound of Formula (III)

-   -   wherein R⁶ is alkyl,    -   and a base to form a compound of Formula (IV)

-   -   wherein R³, R⁴, R⁵ and R⁶ are defined as above; and    -   ii. reducing the compound of Formula (IV) with a reducing agent        to form a compound of Formula (V).

In another embodiment, the base of step i) is LiHMDS, sodium hydride,LDA, KOtBu or NaOEt.

In yet another embodiment, the reducing agent of step ii) is lithiumborohydride, sodium borohydride, disiamylborane, hydrogen with platinum(IV) oxide, hydrogen with palladium/carbon or zinc borohydride. In anembodiment, the reducing agent is sodium borohydride.

In another embodiment, at least one of R³, R⁴ and R⁵ is halogen. Inanother embodiment, the halogen is bromine, chlorine or fluorine. Inanother embodiment, at least one of R³, R⁴ and R⁵ is alkyl. In anotherembodiment, R³ is CH₃ and R⁴ and R⁵ are both fluorine. In anotherembodiment, R³ is Cl and R⁴ and R⁵ are both fluorine. In anotherembodiment, R³ is Br and R⁴ and R⁵ are both fluorine. In anotherembodiment, R³ is CF₃, R⁴ is CH₃O and R⁵ is fluorine. In anotherembodiment, R³ is CH₃ and R⁴ and R⁵ are both chlorine. In anotherembodiment, R³ is CF₃, R⁴ is chlorine and R⁵ is fluorine. In anotherembodiment, R³ and R⁴ are both fluorine R⁵ is hydrogen.

In another embodiment, R³ is CHF₂, R⁴ and R⁵ are fluorine.

In another embodiment, R⁶ is ethyl. In another embodiment, R⁷ is ethyl.In another embodiment, R⁷ is methyl.

DETAILED DESCRIPTION

Compounds of Formula (I) which are analogs of crotonic acid are usefulas intermediates for the production of compounds which are useful asmedicaments.

The syntheses of crotonic acid analogs are known. WO2012/041872,WO2012/041873, WO2013/144179 and WO2013/144180, among others, discloseprocesses to prepare substituted pent-2-enoates and but-2-enoates fromthe corresponding 3-hydroxy-pentanoates and 3-hydroxy-butanoates,respectively.

In these applications, phosphorous pentoxide (P₂O₅) ordiphenyl-2-pyridylphosphine and di-butylazodicarboxylate were used asreagents for these dehydration reactions. Other references havedisclosed the use of triphenylphosphine and diethyl azodicarboxylate(DEAD) or tosyl chloride and triethylamnine as reagents for similarreactions (see Jagodzinska, Bevilaqua, Tamura and Yamazaki above). Thesereagents offer several disadvantages when the process is conducted oncommercial scale.

When triphenylphosphine and diethylazodicarboxylate are used for thedehydration reaction, byproducts (triphenylphosphine oxide anddiethoxycarboxyhydrazine) are formed which make purification of thedesired reaction product difficult. Chromatographic separation is oftenrequired which is undesired and often impractical at a commercial scale.Moreover, diethylazodicarboxylate is an expensive reagent that is lightand oxygen sensitive and thermally unstable which can lead touncontrollable runaway reactions. Transport of this reagent is severelyrestricted and limited to only solutions, not the pure form.Triphenylphosphine is also sensitive against oxygen and air.Furthermore, it generates large waste streams due to an unfavourablemass balance.

Diphenyl-2-pyridylphosphine and di-butylazodicarboxylate have been usedas alternatives to triphenylphosphine and diethylazodicarboxylate forthe dehydration reaction (see WO2013/144179 and WO2013/144180). However,the cost of these reagents is prohibitive for a commercial process.

The phosphorpentoxide reagent (P₂O₅) reagent used in the dehydrationreactions of the cited references (see WO2012/041872 and WO2012/041873)is a solid and was used in the cited references without any solvent. Ona large scale, efficient mixing of solids is not possible. Moreover,when solids are mixed there is little dissipation of generated reactionheat, and this poses a severe safety risk.

Tosylchloride is also a solid and as noted above with P₂O₅ is moredifficult to handle on a larger scale than the scale of the reactionsdisclosed in the cited references (see Tamura et al. and Yamazaki etal.). Furthermore, precautions must be taken to avoid exposure to dust.Liquids are easier to handle on large scale, especially in a productionenvironment.

There is a need for alternative reagents to conduct the dehydrationreaction of substituted 3-hydroxy-pentanoates and 3-hydroxy-butanoatesto form the corresponding pent-2-enoates and but-2-enoates, especiallyon a commercial scale. Applicants have found that methane sulfonylchloride is unexpectedly a suitable reagent for this transformation.

An embodiment of the invention is a process to prepare a compound ofFormula (I)

wherein R³, R⁴ and R⁵ are each selected independently from hydrogen,halogen, alkyl, alkenyl, alkynyl, alkoxyl, and wherein the alkyl,alkenyl, alkynyl, and alkoxyl may be optionally substituted with one ormore halogen, alkyl, alkenyl, alkynyl, and alkoxyl;comprising

-   -   a) reacting a compound of Formula (V)

-   -   wherein R³, R⁴ and R⁵ are defined as above, and R⁶ is alkyl;    -   with methane sulfonyl chloride and a base to form a compound of        Formula (VI)

-   -   wherein R³, R⁴, R⁵ and R⁶ are defined as above; and    -   b) reacting the compound of Formula (VI) with a reagent to form        a compound of Formula (I).

Another embodiment of the process is wherein the base of step a) is anamine. In yet another embodiment, the amine is triethylamine.

Another embodiment of the process is wherein the reagent of step b) isan acid or a base. In yet another embodiment of the process, the reagentis a base. In further embodiments, the base is sodium hydroxide, lithiumhydroxide or potassium hydroxide. In an embodiment, the base is sodiumhydroxide.

Suitable solvents for step b) comprise solvents that are miscible withwater like THF, EtOH, MeOH or isopropanol. In one embodiment, thereaction of step b) is done in a mixture of such a solvent and water.Other suitable solvents comprise solvents that are immiscible with waterlike toluene. In another embodiment, the reaction of step b) is done ina mixture of such a solvent with water such that a biphasic mixture isused.

Suitable reaction temperatures for step b) range from −10° C. to 60° C.In an embodiment, the temperature range is from 0° C. to 25° C. Inanother embodiment, the temperature range is from 25° C. to 40° C. Inanother embodiment, the temperature range is from 40° C. to 50° C.

In step a) methanesulfonic acid chloride is used advantageously inexcess related to (V) in a ratio of 1:1 to 2:1. In other embodiments,the methane sulfonic acid chloride is used in a ratio of 1:1 to 1.5:1 orin a ratio of 1.25:1 to 1.3:1 or in a ratio of 1.05 to 1.1.

The base in step a) is used advantageously in excess related to (V) in aratio of 2:1 to 8:1, In other embodiments, the ratio is 2:1 to 5:1, orthe ratio is 2:1 to 3:1. The reaction of step a) can be performed insuch a way that the base is added in one portion or can be performed ina stepwise manner advantageously compound (V) is combined with 1 to 1.2equivalents of base followed by the addition of MesCl followed byadditional base.

Suitable temperature for the addition of MesCl in step a) ranges from−10° C. to 25° C. In another embodiment, the temperature is from −5° C.to 0° C. In another embodiment the temperature is from 0° C. to 10° C.Following the addition of MesCl, the reaction is stirred at a suitabletemperature to complete formation of the intermediate methane sulfonicester of (V). Suitable temperature for this reaction ranges from 0° C.to 30° C. Afterwards, the remaining excess of base is added. Suitabletemperature for the addition of the excess base ranges from −10° C. to25° C. In another embodiment, the suitable temperature for the additionof the excess base ranges from 0° C. to 25° C. After complete additionof base, the reaction mixture is stirred to allow complete formation ofcompound (VI). Suitable temperature for this stirring period ranges from0° C. to 40° C. In another embodiment, the suitable temperature for thestirring period ranges from 10° C. to 25° C. In another embodiment, thesuitable temperature for the stirring period ranges from 20° C. to 30°C.

Suitable solvents for step a) include halogenated solvents likedichloromethane (DCM), chloroform, dichloroethane and other solventslike tetrahydrofuran (THF), 2-methyl-THF, toluene, benzene, EtOAc. In anembodiment, the solvent is DCM. In another embodiment, the solvent istoluene.

In one embodiment the solvents for steps a) and b) are different. Inanother embodiment, the solvent for step a) is the same as for step b).

In an embodiment, the base used is triethyl amine, the solvent used isDCM and the temperature of the reaction is from 0° C. to 25° C. Inanother embodiment, the base used is triethyl amine, the solvent used isDCM and the temperature of the reaction is from 0° C. to 25° C. and thetriethyl amine is added stepwise, a portion being added before or withthe methane sulfonyl chloride and a portion being added after theaddition of the methane sulfonyl chloride. In another embodiment, thebase used is triethylamine, the solvent used is toluene and thetemperature of the reaction is from 0° C. to 30° C. In yet anotherembodiment, the base used is triethylamine, the solvent used is tolueneand the temperature of the reaction is from 0° C. to 30° C. and thetriethyl amine is added stepwise, a portion being added before or withthe methane sulfonyl chloride and a portion being added after theaddition of the methane sulfonyl chloride.

The raw product (VI) can be purified or used without purification in thenext step. Methods for purification include chromatography on silica ordistillation. In an embodiment, the raw product (VI) is purified bydistillation. In another embodiment, the distillation is at reducedpressure. In another embodiment, the distillation is performed in ashort path distillation equipment. In yet another embodiment, the rawproduct (VI) is used directly in step b)

In an embodiment, the yield for step a) ranges from 40% to 90%. Inanother embodiment, the yield ranges from 50% to 85%. In anotherembodiment, the yield ranges from 60% to 80%.

In an alternative embodiment, the process further comprises a processfor preparing a compound of Formula (V)

wherein R³, R⁴, R⁵, and R⁶ are defined as above;comprising

i) reacting a compound of Formula (II)

-   -   wherein R³, R⁴ and R⁵ are defined as above and R⁷ is alkyl; with        a compound of Formula (III)

-   -   wherein R⁶ is alkyl,    -   and a base to form a compound of Formula (IV)

-   -   wherein R³, R⁴, R⁵ and R⁶ are defined as above; and    -   ii) reducing the compound of Formula (IV) with a reducing agent        to form a compound of Formula (V).

In another embodiment, the base of step i) is LiHMDS, sodium hydride,LDA, KOtBu or NaOEt.

Step i) is preferably done in a solvent. The solvent can be anether-derived solvent like diethyl ether, methyl tert-butyl ether, THF,2-methyl-THF, 1,4-dioxane or cyclopentyl methyl ether or a hydrocarbonsolvent like toluene. The reaction temperature can range from −78° C. to80° C., preferably from 0° C. to 65° C. In an embodiment the temperatureranges from 50° C. to 60° C. The raw product of compound (IV) istypically subjected to an aqueous quench or work-up which can includethe addition of a solution of an acid like hydrochloride acid orammonium chloride or the addition of a base like sodium carbonate orsodium bicarbonate or the simultaneous addition of an acid and a base.Following the quench or work-up, the raw product (IV) can be useddirectly in step ii). In another embodiment, compound (IV) is isolatedand then used in step ii). In yet another embodiment, compound (IV) isisolated and purified by distillation or column chromatography and thenused in step ii).

In yet another embodiment, the reducing agent of step ii) is lithiumborohydride, sodium borohydride, disiamylborane, hydrogen with platinum(IV) oxide, hydrogen with palladium/carbon or zinc borohydride. In anembodiment, the reducing agent is sodium borohydride.

Suitable solvents for step ii) include ether-derived solvent likediethyl ether, methyl tert-butyl ether, THF, 2-methyl-THF, 1,4-dioxaneor cyclopentyl methyl ether or inert solvents like toluene. In oneembodiment the solvents for steps i) and ii) are different. In anotherembodiment, the solvent for step i) is the same as for step ii).

The reducing agent for step ii) is added at a temperature that can rangefrom −10° C. to 25° C. In an embodiment, the addition is done at 0° C.,in another embodiment the addition is done at a temperature from 20° C.to 25° C. After the addition of the reducing agent, the reaction in stepii) is continued at a temperature that ranges from −10° C. to 25° C. Inone embodiment, the reaction is continued at 0° C., in anotherembodiment the reaction is continued at a temperature from 20° C. to 25°C.

In another embodiment, steps i), ii), a) and b) of the process areconducted without isolation of the intermediate compounds of Formulas(IV), (V) or (VI).

In another embodiment, at least one of R³, R⁴ and R⁵ is halogen. In yetother embodiments, the halogen is bromine, chlorine or fluorine.

In further embodiments, at least one of R³, R⁴ and R⁵ is alkyl. Inanother embodiment, R³ is CH₃ and R⁴ and R⁵ are both fluorine. In yetanother embodiment, R³ is Cl and R⁴ and R⁵ are both fluorine. In anotherembodiment, R³ is Br and R⁴ and R⁵ are both fluorine. In an embodiment,R³ is CF₃, R⁴ is CH₃O and R⁵ is fluorine. In yet another embodiment, R³is CH₃ and R⁴ and R⁵ are both chlorine. In another embodiment, R³ isCF₃, R⁴ is chlorine and R⁵ is fluorine.

In an embodiment, R⁶ is ethyl. In another embodiment, R⁷ is ethyl. Inyet another embodiment, R⁷ is methyl.

The following definitions are provided to more clearly describe theinvention.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.In one embodiment alkyl groups contain about 1 to about 12 carbon atomsin the chain. In another embodiment alkyl groups contain about 1 toabout 6 carbon atoms in the chain. Branched means that one or more loweralkyl groups such as methyl, ethyl or propyl, are attached to a linearalkyl chain. “Lower alkyl” means a group having about 1 to about 6carbon atoms in the chain which may be straight or branched.Non-limiting examples of suitable alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, ordecyl.

“Alkylene” means a divalent group obtained by removal of a hydrogen atomfrom an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene. In one embodiment,alkylene groups have about 1-18 carbon atoms in the chain, which may bestraight or branched. In another embodiment, alkylene groups have about1-12 carbon atoms in the chain, which may be straight or branched. Inanother embodiment, alkylene groups may be lower alkylenes. “Loweralkylene” means an alkylene having about 1 to 6 carbon atoms in thechain, which may be straight or branched.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. In oneembodiment alkenyl groups have about 2 to about 12 carbon atoms in thechain. In another embodiment alkenyl groups have about 2 to about 6carbon atoms in the chain. Branched means that one or more lower alkylgroups such as methyl, ethyl or propyl, are attached to a linear alkenylchain. “Lower alkenyl” means about 2 to about 6 carbon atoms in thechain which may be straight or branched. The term “substituted alkenyl”means that the alkenyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, aryl,cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limiting examples ofsuitable alkenyl groups include ethenyl, propenyl, n-butenyl,3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. In oneembodiment alkynyl groups have about 2 to about 12 carbon atoms in thechain. In another embodiment alkynyl groups have about 2 to about 4carbon atoms in the chain. Branched means that one or more lower alkylgroups such as methyl, ethyl or propyl, are attached to a linear alkynylchain. “Lower alkynyl” means about 2 to about 6 carbon atoms in thechain which may be straight or branched. Non-limiting examples ofsuitable alkynyl groups include ethynyl, propynyl, 2-butynyl,3-methylbutynyl, n-pentynyl, and decynyl. The term “substituted alkynyl”means that the alkynyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of alkyl, aryl andcycloalkyl.

“Halo” (or “halogeno” or “halogen”) means fluoro, chloro, bromo, or iodogroups. Preferred are fluoro, chloro or bromo, and more preferred arefluoro and chloro.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl are replaced by a halo group as defined above.

“Alkoxy” means an —O-alkyl group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.The bond to the parent moiety is through the ether oxygen.

With reference to the number of moieties (e.g., substituents, groups orrings) in a compound, unless otherwise defined, the phrases “one ormore” and “at least one” mean that there can be as many moieties aschemically permitted, and the determination of the maximum number ofsuch moieties is well within the knowledge of those skilled in the art.

When used herein, the term “independently”, in reference to thesubstitution of a parent moiety with one or more substituents, meansthat the parent moiety may be substituted with any of the listedsubstituents, either individually or in combination, and any number ofchemically possible substituents may be used.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. Non-limiting examples of suitablesolvates include ethanolates, methanolates, and the like. “Hydrate” is asolvate wherein the solvent molecule is H₂O.

The term “salt(s)”, as employed herein, denotes acidic salts formed withinorganic and/or organic acids, as well as basic salts formed withinorganic and/or organic bases.

TEA is triethylamine.DCM is dichloromethane.THF is tetrahydrofuran.EtOH is ethanol.MeOH is methanol.EtOAc is ethyl acetate.Mesyl chloride or MesCl or MSC means methane sulfonyl chloride ormethanesulfonic acid chloride.Tosyl chloride means p-toluene sulfonyl chloride.Reducing agent—Non-limiting examples of reducing agents are lithiumborohydride, sodium borohydride, disiamylborane, hydrogen withplatinum(IV) oxide, hydrogen with palladium/carbon, zinc borohydride andthe like.

Examples Example 1: Synthesis of (E)-4-bromo-4,4-difluoro-but-2-enoicacid

Step A: Ethyl 4-bromo-4,4-difluoro-3-oxo-butanoate

Lithium bis(trimethylsilyl)amide (200 ml of a 1M solution in THF, 0.2mol) was cooled to −75° C. with stirring. A mixture of ethyl acetate (17ml, 0.19 mol) and THF (15 ml) was charged with stirring over one hourwhile keeping the temperature at −75° C. A mixture of ethyl2-bromo-2,2-difluoroacetate (20 g, 0.099 mol) and THF (20 ml) wascharged over one hour at the same temperature. The reaction mixture wasquenched with a saturated aqueous solution of NH₄Cl (150 ml) forming aslurry, the cooling bath was removed and the reaction mixture wasallowed to reach room temperature overnight while stirring wascontinued. The mixture was acidified with aqueous HCl (1M) and thelayers separated. The aqueous layer was extracted with EtOAc, theorganic phases were combined, washed two times with aqueous HCl (1M) andwith brine, dried over MgSO₄ and concentrated under reduced pressure.The residue was distilled under reduced pressure (6 mbar, 75° C.) toyield 19.1 gram (79% yield). ¹H-NMR (600 MHz, CDCl₃): δ 11.94 (s), 5.46(s), 4.19 (q, J=7.1 Hz), 4.16 (q, J=7.2 Hz), 3.71 (s), 1.24 (t, J=7.1Hz), 1.21 (t, J=7.1 Hz), ¹⁹F-NMR (564 MHz, CDCl₃): δ −59.1 (s), −65.0(s)

Step B: Ethyl 4-bromo-4,4-difluoro-3-hydroxy-butanoate

Ethyl 4-bromo-4,4-difluoro-3-oxo-butanoate (18 g from step A, 0.073 mol)was dissolved in toluene (200 ml) and cooled in an ice bath. Sodiumborohydride (3.03 g, 0.08 mol) was charged portionwise with stirring.After 15 minutes, the ice bath was removed and the mixture was allowedto reach room temperature overnight while stirring was continued. Themixture was filtered, the filter residue washed with toluene, thefiltrates were combined, cooled in an ice bath and acidified with HCl(1M). The layers were separated and the aqueous layer was extracted withEtOAc (2 times). The combined organic layers were washed with brine,dried over MgSO₄ and concentrated under reduced pressure. The residuewas dissolved in methanol and the mixture evaporated to dryness to yield16.35 gram (90% yield). ¹H-NMR (600 MHz, CDCl₃): δ 4.27-4.37 (m, 1H),4.13 (q, J=7.1 Hz, 1H), 2.71 (dd, J=16 Hz, 3.1 Hz, 1H), 2.59 (dd, J=16Hz, 9 Hz, 1H), 1.21 (t, J=7.1 Hz, 3H); ¹⁹F-NMR (564 MHz, CDCl₃): δ −57.4(dd, J=165 Hz, 8 Hz), −60.0 (dd, J=164 Hz, 8 Hz); MS 201, 203[M-OC₂H₅]⁺.

Step C: Ethyl (E)-4-bromo-4,4-difluoro-but-2-enoate

Ethyl 4-bromo-4,4-difluoro-3-hydroxy-butanoate (15.3 g from step B,0.062 mol) was combined with DCM (200 ml) and TEA (8.6 ml, 0.062 mol)and cooled in an ice bath. A solution of methanesulfonic acid chloride(7.24 ml, 0.093 mol) in DCM (50 ml) was charged with stirring while thetemperature was kept between 5° C. and 10° C. After the addition wascomplete, the cooling bath was removed and the mixture was stirred atambient temperature for 4 hours. The mixture was cooled in an ice bathand TEA (17.3 ml, 0.124 mol) was charged dropwise. After the additionwas complete, the cooling bath was removed and the mixture was stirredovernight at ambient temperature. Water (50 ml) was added to the mixturewith stirring, the layers were separated. The organic layer was washedwith HCl (1N, 50 ml, 2 times), brine, dried over MgSO₄ and concentratedunder reduced pressure. The residue was distilled under reduced pressure(4.5 mbar, 70° C.) to yield 10.9 g (77% yield). ¹H-NMR (600 MHz, CD₃CN):δ 6.97 (dt, J=16 Hz, 10 Hz, 1H), 6.27 (dt, J=16 Hz, 2 Hz, 1H), 4.13 (q,J=7.1 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H), ¹⁹F-NMR (564 MHz, CD₃CN): 6-50.3(d, J=11 Hz), MS 183, 185 [M-OC₂H₅]⁺.

Step D: (E)-4-bromo-4,4-difluoro-but-2-enoic acid

NaOH (4M, 19 ml, 0.076 mol) was added to a mixture of ethyl(E)-4-bromo-4,4-difluoro-but-2-enoate (9.9 g of step C, 0.043 mol) inEtOH (50 ml) and stirred at ambient temperature for two hours. Themixture was acidified with HCl (6M, 18 ml). EtOAc (80 ml) was added andafter 5 minutes of stirring phase separation was observed. The layerswere separated, the organic layer was washed with brine, dried overMgSO₄ and concentrated under reduced pressure to yield 7.84 g of a solid(90% yield). ¹H-NMR (300 MHz, CD₃CN): δ 7.07 (dt, J=16 Hz, 10 Hz, 1H),6.36 (dt, J=16 Hz, 2 Hz, 1H), ¹⁹F-NMR (282 MHz, CD₃CN): 6-50.3 (d, J=10Hz), MS 199, 201 (M−1).

Example 2: Synthesis of (E)-4,4-difluorobut-2-enoic acid

Step A: Ethyl 4,4-difluoro-3-oxo-butanoate

Sodium hydride (60% dispersion in mineral oil, 10.7 g, 0.267 mol) wassuspended in THF (anhydrous, 300 ml) under a nitrogen atmosphere. Themixture was cooled to 0° C. with stirring, ethyl acetate (26 ml, 0.267mol) was charged over 20 min and stirring was continued for one hour.Ethyl 2,2-difluorobutanoate (16.1 g, 0.13 mol) was dissolved in THF(anhydrous, 20 ml) and this solution was charged with stirring over 20min while the temperature was kept at 0° C. Stirring was continued forthree hours at 0° C., the cooling bath was removed and the mixturestirred at room temperature for two days. The mixture was cooled to 0°C. and quenched with a saturated aqueous solution of NH₄Cl (60 ml)forming a slurry. Hydrochloric acid was added (2M, 60 ml), the layerswere separated, and the aqueous layer was extracted with diethylether(50 ml, three times). The combined organic layers were washed two timeswith hydrochloric acid (2M), brine, dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was distilled under reduced pressure(25 mbar, 52-62° C.) to yield 16.4 gram of a liquid (0.099 mol, 76%yield). ¹H-NMR (300 MHz, CDCl₃): δ 11.8 (s), 5.72-6.22 (m), 5.50 (s),4.21-4.31 (m), 3.71 (m), 1.27-1.35 (m); ¹⁹F-NMR (282 MHz, CDCl₃): δ−126.4 (d, J=54 Hz), −127.8 (d, J=53 Hz); MS 121 (M-OCH₂CH₃)

Step B: Ethyl 4,4-difluoro-3-hydroxy-butanoate

Ethyl 4,4-difluoro-3-oxo-butanoate (16 g from step A, 0.096 mol) wasdissolved in toluene (250 ml) and cooled in an ice bath. Sodiumborohydride (4 g, 0.106 mol) was charged portionwise with stirring.After 15 minutes, the ice bath was removed and the mixture was allowedto reach room temperature overnight while stirring was continued. Themixture was filtered, the filter residue washed with toluene, thefiltrates were combined, cooled in an ice bath and acidified with HCl(1M). The layers were separated and the aqueous layer was extracted withEtOAc (2 times). The combined organic layers were washed with brine,dried over MgSO₄ and concentrated under reduced pressure. The residuewas dissolved in methanol and the mixture evaporated to dryness to yield9 gram of a liquid (0.053 mol, 56% yield). ¹H-NMR (300 MHz, CDCl₃): δ5.78 (td, J=56 Hz, 3.7 Hz, 1H), 4.32 (m, 1H), 4.13 (q, J=7.1 Hz, 2H),2.71 (m, 1H), 2.59 (m, 1H), 1.21 (t, J=7.1 Hz, 3H); ¹⁹F-NMR (282 MHz,CDCl₃): δ −128.7 (ddd, J=288 Hz, 56 Hz, 10 Hz), −131.7 (ddd, J=288 Hz,56 Hz, 12 Hz); MS 123 (M-OCH₂CH₃)

Step C: Ethyl (E)-4,4-difluoro-but-2-enoate

Ethyl 4,4-difluoro-3-hydroxy-butanoate (9 g from step B, 0.053 mol) wasdissolved in DCM (100 ml) followed by the addition of TEA (7.46 ml,0.053 mol) and cooled in an ice bath. A solution of methanesulfonic acidchloride (6.26 ml, 0.08 mol) in DCM (25 ml) was added dropwise withstirring while the temperature was kept between 0° C. and 5° C. Afterthe addition was complete, the cooling bath was removed and the mixturewas stirred at ambient temperature for 4 hours. The mixture was cooledin an ice bath and TEA (14.9 ml, 0.107 mol) was added dropwise. Afterthe addition was complete, the cooling was removed and the mixture wasstirred overnight at ambient temperature. Water (50 ml) was added to themixture with stirring, the layers were separated. The organic layer waswashed with HCl (1N, 50 ml, 3 times), brine, dried over MgSO₄ andconcentrated under reduced pressure. The residue was distilled underreduced pressure (37 mbar, 58-60° C.) to yield 3.6 g (0.022 mol, 40%yield). ¹H-NMR (300 MHz, CDCl₃): δ 6.75-6.85 (m, 1H), 6.29 (dt, J=16 Hz,2.9 Hz, 1H), 6.14 (td, J=55 Hz, 4.2 Hz, 1H), 4.26 (q, J 7.1 Hz, 2H),1.32 (t, J=7.1 Hz, 3H), ¹⁹F-NMR (282 MHz, CD₃Cl): δ −115.9 (ddd, J=54Hz, 10 Hz, 3.0 Hz), MS 183, 185 [M-OC₂H₅]⁺.

Step D: (E)-4,4-difluoro-but-2-enoic acid

Ethyl (E)-4,4-difluoro-but-2-enoate (3.6 g from step C, 0.024 mol) wasdissolved in THF (24 ml) and cooled down to 0° C. in an ice-bath. NaOH(4N, 14 ml) was charged in one portion. The mixture was stirred for 3 hat room temperature. The layers were separated and the organic layer wasextracted with NaOH (2M). The combined aqueous layers were cooled againin an ice-bath, acidified to pH 1 with hydrochloric acid (6N) and thenextracted with ethyl acetate (2 times). The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated under reducedpressure. The residue was dissolved in methyl tert-butyl ether, washedwith HCl (1N, 2 times) and then extracted with NaOH (2N, 4 times). Thecombined aqueous extracts were washed with methyl tert-butyl ether (3times), acidified with HCl (10%) and extracted with methyl tert-butylether (4 times). The combined organic extracts were dried over Na₂SO₄and evaporated under reduced pressure to yield 2.22 g (0.0182 mol, 76%).¹H-NMR (300 MHz, CDCl₃): δ 11.70 (s), 6.83 (ddt, J=16 Hz, 10 Hz, 4 Hz,1H), 6.22 (ddt, J=16 Hz, 3 Hz, 1 Hz, 1H), 6.18 (ddt, J=55 Hz, 4 Hz, 1Hz, 1H); ¹⁹F-NMR (282 MHz, CD₃Cl): δ −116.8 (ddd, 54 Hz, 10 Hz, 3 Hz);MS 121 (M-H).

Example 3: Synthesis of (E)-4,4,5,5,5-pentafluoropent-2-enoic acid

Step A: Ethyl 4,4,5,5,5-pentafluoro-3-oxo-pentanoate

Sodium ethoxide (7.49 g, 0.11 mol) was suspended in methyl tert-butylether (anhydrous, 200 ml) under nitrogen. Ethyl2,2,3,3,3-pentafluoropropanoate (14.8 ml, 0.1 mol) was added dropwisewith stirring followed by ethyl acetate (10.7 ml, 0.11 mol). Stirringwas continued for 45 minutes at ambient temperature, for one hour at 50°C. and overnight at ambient temperature. The mixture was cooled to 0° C.and acidified with HCl (1M, 80 ml), brine was added (80 ml), the layerswere separated, and the aqueous layer was back-extracted with in methyltert-butyl ether (80 ml). The combined organic layers were dried overNa₂SO₄ and concentrated under reduced pressure to yield 14.6 gram (0.062mol, 62% yield). ¹H-NMR (300 MHz, CDCl₃): δ 11.96 (s), 5.59 (s),4.11-4.26 (m), 3.70 (m), 1.21-1.29 (m); ¹⁹F-NMR (282 MHz, CDCl₃): δ−81.8 (s), −83.3 (s), −122.7 (s), −123.6 (s); MS 189 (M-OCH₂CH₃)

Step B: Ethyl 4,4,5,5,5-pentafluoro-3-hydroxy-pentanoate

Ethyl 4,4,5,5,5-pentafluoro-3-oxo-pentanoate (14.6 g from step A, 0.062mol) was dissolved in toluene (250 ml) and cooled in an ice bath. Sodiumborohydride (2.6 g, 0.069 mol) was added portionwise with stirring.After 15 minutes, the ice bath was removed and the mixture was allowedto reach room temperature overnight while stirring was continued. Themixture was filtered, the filter residue washed with toluene, thefiltrates were combined, cooled in an ice bath and acidified with HCl(1M). The layers were separated and the aqueous layer was extracted withEtOAc (2 times). The combined organic layers were washed with brine,dried over MgSO₄ and concentrated under reduced pressure. The residuewas dissolved in methanol and the mixture evaporated to dryness to yield11.3 gram of a liquid (0.048 mol, 77% yield). ¹H-NMR (300 MHz, CDCl₃): δ4.43-4.55 (m, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.86 (s, 1H), 2.59-2.71 (m,2H), 1.22 (t, J=7.1 Hz, 3H); ¹⁹F-NMR (282 MHz, CDCl₃): δ −81.9 (s),−122.7 (dd, J=276 Hz, 5.8 Hz), −131.4 (dd, J=276 Hz, 18 Hz); MS 191(M-OCH₂CH₃)

Step C: Ethyl (E)-4,4,5,5,5-pentafluoro-pent-2-enoate

Ethyl 4,4,5,5,5-pentafluoro-3-hydroxy-pentanoate (11.3 g from step B,0.048 mol) was combined with DCM (120 ml) and TEA (6.67 ml, 0.048 mol)and cooled in an ice bath. A solution of methanesulfonic acid chloride(5.59 ml, 0.072 mol) in DCM (30 ml) was added dropwise with stirringwhile the temperature was kept between 0° C. and 5° C. After theaddition was complete, the cooling bath was removed and the mixture wasstirred at ambient temperature for 4 hours. The mixture was cooled in anice bath and TEA (13.34 ml, 0.096 mol) was added dropwise. After theaddition was complete, the cooling was removed and the mixture wasstirred overnight at ambient temperature. Water (60 ml) was added to themixture with stirring, the layers were separated. The organic layer waswashed with HCl (1N, 50 ml, 3 times) and brine, dried over MgSO₄ andconcentrated under reduced pressure. The residue was distilled underreduced pressure (50 mbar, 55° C.) to yield 6.5 g of an oil (0.03 mol,62% yield). ¹H-NMR (300 MHz, CDCl₃): δ 6.73 (dt, J=16 Hz, 12 Hz, 1H),6.47 (dt, J=16 Hz, 2.0 Hz, 1H), 4.21 (q, J 7.1 Hz, 2H), 1.26 (t, J=7.1Hz, 3H), ¹⁹F-NMR (282 MHz, CD₃Cl): δ −84.8 (s), −117.2 (m); MS 173(M-OC₂H₅).

Step D: (E)-4,4,5,5,5-pentafluoropent-2-enoic acid

(E)-Ethyl 4,4,5,5,5-pentafluoropent-2-enoate (6.5 g from step C, 0.03mol) was dissolved in THF (30.0 ml) and cooled down to 0° C. in anice-bath. NaOH (4N, 18 ml, 0.072 mol) was charged in one portion. Themixture was stirred for 3 h at room temperature. Then the layers wereseparated and the organic layer was extracted with NAOH (2M, 50 ml). Thecombined aqueous layers were cooled again in an ice-bath, acidified topH 1 with hydrochloric acid (6N) and then extracted with ethyl acetate(50 ml, 2 times). The combined organic layers were washed with brine (50ml), dried over Na₂SO₄ and concentrated under reduced pressure to yield4 g of a solid (0.02 mol, 70%). ¹H-NMR (300 MHz, CDCl₃): δ 6.84 (dt,J=16 Hz, 12 Hz, 1H), 6.50 (dt, J=16 Hz, 2 Hz, 1H); ¹⁹F-NMR (282 MHz,CD₃Cl): δ −84.6 (s), −117.5 (d, 11 Hz), MS 189 (M-H).

Example 4

Additional compounds that were synthesized using the procedure of Step Cin Examples 1-3 above are presented in Table 1 below. Differences in thepurification of the compounds of Formula (VI) are described in thecolumn “Purification”. The starting materials for the below compoundswere prepared generally as described in Steps A and B in Examples 1-3above.

TABLE 1 Purification of Yield % for R³ R⁴ R⁵ (VI) step (V) to (VI) ¹HNMR of (I) MS Cl F F as in examples 76 (400 MHz; CDCl3) δ 7.05 (dt, J =16 Hz, 155 (M − H) above 9 Hz, 1H), 6.42 (dt, J = 16 Hz, 2 Hz, 1H) Me FF as in examples 75 (300 MHz; DMSO-d₆) δ 6.83 (dt, J = 16 Hz, 137 (M +H) above 11 Hz 1H), 6.23 (dt, J = 16 Hz, 3 Hz, 1H), 1.79 (t, J = 19 Hz,3H) CF₃ OMe F Chromatography 45 (400 MHz; DMSO-d₆) δ 6.71 (dd, J = 18Hz, 133 (M − CF₃) on silica column 16 Hz, 1H), 6.44 (d, J = 16 Hz, 1H),3.49 (d, J = 1 Hz, 3H) Me Cl Cl Chromatography 58 (400 MHz; DMSO-d₆) δ13.04 (s, 133 (M − Cl) on silica column 1H), 7.08 (d, J = 15 Hz, 1H),6.17 (d, J = 15 Hz, 1H), 2.33 (s, 3H) CF₃ Cl F Chromatography 91 (400MHz; DMSO-d₆) δ 13.49 (s, 171 (M − Cl) on silica column 1H), 6.99 (dd, J= 18 Hz, 16 Hz, 1H), 6.55 (d, J = 16 Hz, 1H) CHF₂ F F Filtration through80 (300 MHz); DMSO-d6) δ 13.2 (s, silica 1H), 6.82 (dt, J = 16 Hz, 12Hz, 1H), 6.64 (tt, J = 52 Hz, 4 Hz, 1H), 6.48 (dt, J = 16 Hz, 2 Hz, 1H)

The compounds (VI) of Table 1 were subsequently reacted as in Step D ofExamples 1-3 above to produce the analogous enoic acid compounds (I).

Example 5: Synthesis of (E)-4,4-difluoropent-2-enoic acid

Step A: Ethyl 4,4-difluoro-3-oxo-pentanoate

Sodium hydride (14.5 g, 0.36 mol), toluene (120 ml) and ethyl acetate(2.9 ml, 0.029 mol) were combined under an atmosphere of nitrogen andheated to 50° C. Ethanol (1.7 ml, 0.03 mol) was added dropwise and theresulting slurry was stirred for 5 min. A mixture of ethyl2,2-difluoropropanoate (40 g, 0.29 mol) and ethyl acetate (31.4 ml, 0.32mol) was charged over 90 min with stirring keeping the temperaturebetween 50 and 55° C. Stirring was continued for one hour aftercompletion of addition. The mixture was allowed to reach roomtemperature and quenched by the parallel addition of aqueous sodiumbicarbonate (0.72 M, 80 ml) and HCl (conc., ca. 20 ml) keeping the pHbetween 7.5 and 9.5. The resulting mixture was carried to Step B.

Step B: Ethyl 4,4-difluoro-3-hydroxy-pentanoate

The pH of the mixture from Step A was adjusted to 7.5 to 8.5 with conc.HCl. Subsequently, sodium borohydride (3.29 g, 0.087 mol) was added inportions while keeping the temperature between 15 and 25° C. and the pHbelow 9.5. After completion of addition the mixture was stirred for 1hour. The pH was adjusted to 4-5 by the addition of conc. HCl and thelayers were separated. The organic layer was washed with a solution of 1g sodium bicarbonate in brine (50 ml), filtered through a short plug ofmagnesium sulfate, concentrated under reduced pressure to a volume ofca. 150 ml and carried to Step C.

Step C: Ethyl (E)-4,4-difluoropent-2-enoate

The residue of Step B was diluted with toluene (300 ml) and cooled to 0°C. Methanesulfonylchloride (20.8 ml, 0.267 mol) was added followed bycharging of triethylamine (39.1 ml, 0.28 mol) over 90 min while keepingthe temperature below 10° C. Toluene (100 ml) was charged followed bytriethylamine (50 ml, 0.357 mol) and the mixture was stirred overnightat room temperature. Water (100 ml) was added, the mixture was stirreduntil precipitates dissolved, the phases were separated and the organicphase was carried to Step D.

Step D: (E)-4,4-difluoropent-2-enoic acid

Water (40 ml) was charged to the residue of Step C and the mixture wasstirred at 40 to 45° C. Aqueous NaOH (37 ml, 30%) was charged over 90min keeping the temperature between 40 and 45° C. Stirring was continuedfor 90 min at this temperature, then heating was turned off and stirringwas continued at room temperature for 72 hours. The phases wereseparated, the organic was phase back-extracted with water. From thecombined aqueous phases ca. 20 ml were distilled off under reducedpressure. EtOH (15 ml) was added, the mixture was stirred at 0 to 10°C., the pH was adjusted to 2.5 to 3 with conc. HCl and the mixture wasstirred for 30 min at this temperature. The pH was adjusted to 1.3 to1.6 with conc. HCl, and the mixture was stirred at −4 to −10° C. for onehour. The precipitate was isolated by filtration, washed with water/EtOH(precooled, 80:20, 2×30 ml) and dried under reduced pressure to give22.2 g of a solid (yield 56% for Steps A-D combined).

¹H-NMR (300 MHz; DMSO-d6) δ 12.99 (s, 1H), 6.83 (dt, J=16 Hz, 11 Hz,1H), 6.23 (dt, J=16 Hz, 3 Hz, 1H), 1.79 (t, J=19 Hz, 3H), MS 271.0(2M-H)

1. A process to prepare a compound of Formula (I)

wherein R³, R⁴ and R⁵ are each selected independently from hydrogen,halogen, alkyl, alkenyl, alkynyl, alkoxyl, and wherein the alkyl,alkenyl, alkynyl, and alkoxyl may be optionally substituted with one ormore halogen, alkyl, alkenyl, alkynyl, and alkoxyl; comprising a)reacting a compound of Formula (V)

wherein R³, R⁴ and R⁵ are defined as above, and R⁶ is alkyl; withmethane sulfonyl chloride and a base to form a compound of Formula (VI)

wherein R³, R⁴, R⁵ and R⁶ are defined as above; and b) reacting acompound of Formula (VI) with a reagent to form a compound of Formula(I).
 2. The process of claim 1, wherein the base of step a) is an amine.3. The process of claim 1, wherein the reagent of step b) is an acid ora base.
 4. The process of claim 3, wherein the base is sodium hydroxide,lithium hydroxide or potassium hydroxide.
 5. The process of claim 1,further comprising the steps for preparing a compound of Formula (V)

wherein R³, R⁴, R⁵, and R⁶ are defined as above; comprising i. reactinga compound of Formula (II)

wherein R³, R⁴ and R⁵ are defined as above and R⁷ is alkyl; with acompound of Formula (III)

wherein R⁶ is alkyl, and a base to form a compound of Formula (IV)

wherein R³, R⁴, R⁵ and R⁶ are defined as above; and ii. reducing thecompound of Formula (IV) with a reducing agent to form a compound ofFormula (V).
 6. The process of claim 5, wherein the steps i), ii), a)and b) are conducted without isolation of the intermediate compounds ofFormulas IV, V or VI.
 7. The process of claim 5, wherein the base ofstep i) is LiHMDS, sodium hydride, LDA, KOtBu or NaOEt.
 8. The processof claim 5, wherein the reducing agent of step ii) is lithiumborohydride, sodium borohydride, disiamylborane, hydrogen with platinum(IV) oxide, hydrogen with palladium/carbon or zinc borohydride.
 9. Theprocess of claim 1, wherein at least one of R³, R⁴ and R⁵ is halogen.10. The process of claim 9, wherein the halogen is bromine, chlorine orfluorine.
 11. The process of claim 1, wherein at least one of R³, R⁴ andR⁵ is alkyl.
 12. The process of claim 1, wherein R³ is CH₃ and R⁴ and R⁵are both fluorine.
 13. The process of claim 1, wherein R⁶ is ethyl. 14.The process of claim 5, wherein R⁷ is methyl or ethyl.
 15. The processof claim 1, wherein R³ is Cl and R⁴ and R⁵ are both fluorine.
 16. Theprocess of claim 1, wherein R³ is Br and R⁴ and R⁵ are both fluorine.17. The process of claim 1, wherein R³ is CF₃, R⁴ is CH₃O and R⁵ isfluorine.
 18. The process of claim 1, wherein R³ is CH₃ and R⁴ and R⁵are both chlorine.
 19. The process of claim 1, wherein R³ is CF₃, R⁴ ischlorine and R⁵ is fluorine.
 20. The process of claim 2, wherein theamine is triethylamine.